Lung tumor genomes more unstable in nonsmokers vs smokers

DNA extracted from lung adenocarcinomas revealed that on average, lung tumors in never-smokers showed higher frequencies of copy number alterations and greater proportions of altered genomes compared with those of smokers.

“The discovery that there are different patterns of genetic alterations in smokers and never-smokers suggests that lung cancers in these cohorts are likely distinct diseases driven by different molecular mechanisms, and thus may require different treatments,” reported principal investigator Kelsie Thu, a researcher at the BC Cancer Agency Research Centre in Vancouver, Canada, in a statement issued by the International Association for the Study of Lung Cancer (IASLC). The research was presented at the IASLC 14th World Conference on Lung Cancer, held in Amsterdam, the Netherlands, July 3-7, 2011.

According to the IASLC, up to 25% of lung cancer cases worldwide occur in people who have never smoked; traits of those cancers differ from those of lung cancer in smokers. In never-smokers, lung cancer is more likely to be diagnosed as adenocarcinoma, to afflict women and Asians, to have a higher incidence of epidermal growth factor receptor (EGFR) gene mutations, and to have better responses to EGFR-targeting drugs. The few known differences between lung cancers in smokers and never-smokers were clinical features or genetic alterations at only a few specific genes. Thu and colleagues used a whole-genome approach to investigate all the genes in the genome simultaneously. 

The researchers extracted DNA from lung adenocarcinomas and matched nonmalignant tissues from 30 never-smokers, 14 former smokers, and 39 current smokers. After assessing the DNA for EGFR and KRAS gene mutations, the team generated copy number profiles for each tumor using matched nonmalignant lung tissue as a baseline for the identification of somatic copy number alterations. Two independent, public datasets were used to validate the results.

“We identified several genomic regions that were differentially altered in the lung tumor genomes of smokers and never smokers,” reported Thu. “We also found that a greater fraction of lung tumor DNA harbored genetic alterations in never smokers compared to smokers.”

The difference in the higher frequencies of copy number alterations and greater proportions of altered genomes in never-smokers compared with smokers was even more pronounced when former smokers were excluded and never-smokers were compared only to current smokers.

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